One of the most well-known and widely used class of antibacterial agents are the so-called .beta.-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (.beta.-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the .beta.-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given .beta.-lactam antibiotic results because the microorganism produces a .beta.-lactamase. The latter substances are enzymes which cleave the .beta.-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit .beta.-lactamases, and when a .beta.-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain .beta.-lactamase producing microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a .beta.-lactamase inhibiting substance and a .beta.-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components against .beta.-lactamase producing microorganisms.
The present invention relates to a series of 6.beta.-hydroxyalkylpenicillanic acids and esters thereof readily hydrolyzable in vivo which are potent inhibitors of microbial .beta.-lactamases and which enhance the effectiveness of .beta.-lactam antibiotics. The invention further relates to benzyl 6.beta.-hydroxyalkylpenicillanates, said esters being useful chemical intermediates to the corresponding acids.
Pharmaceutical compositions comprising the above-mentioned 6.beta.-substituted penicillanic acids and readily hydrolyzable esters thereof with certain .beta.-lactam antibiotics as well as a method for increasing the effectiveness of certain .beta.-lactam antibiotics in combination with the above-mentioned 6.beta.-substituted penicillanic acids and readily hydrolyzable esters thereof are also parts of the present invention.
Di Ninno, et. al., [J. Org. Chem., 42, 2960 (1977)] have reported the synthesis of 6.beta.-hydroxyalkylpenicillanic acids and the corresponding benzyl esters as potential antibacterial agents and useful intermediates, respectively.
6-Ethylpenicillanic acid and its sulfoxide derivative are claimed as antibiotics in U.S. Pat. No. 4,123,539.
6.alpha.-Hydroxypenicillanic acid and esters thereof have been prepared from 6-diazopenicillanic acid and the corresponding esters [J. Org. Chem., 39 1444 (1974)].
U.S. Pat. No. 4,143,046 discloses 6.beta.-substituted sulfonyloxypenicillanic acids as antibacterial agents.